Integrated catalytic protection of oxidation sensitive materials

ABSTRACT

An implantable device with in vivo functionality, where the functionality of the device is negatively affected by ROS typically associated with inflammation reaction as well as chronic foreign body response as a result of tissue injury, is at least partially surrounded by a protective material, structure, and/or a coating that prevents damage to the device from any inflammation reactions. The protective material, structure, and/or coating is a biocompatible metal, preferably silver, platinum, palladium, gold, manganese, or alloys or oxides thereof that decomposes reactive oxygen species (ROS), such as hydrogen peroxide, and prevents ROS from oxidizing molecules on the surface of or within the device. The protective material, structure, and/or coating thereby prevents ROS from degrading the in vivo functionality of the implantable device.

This application claims the benefit of prior-filed provisional patentapplication U.S. 61/452,893 which was filed on Mar. 15, 2011, and alsoclaims the benefit of prior-filed provisional patent application U.S.61/527,368 which was filed on Aug. 25, 2011, the contents of both ofwhich are hereby incorporated by reference in their entireties. Thisinvention was not made with government support under any governmentcontract awarded by any Federal agency, and thus the government does notretain rights in the invention.

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to the catalytic protection of materialsand devices that are sensitive to oxidation by integrating the catalyticprotection with the material or device. The present inventionparticularly relates to devices designed to be implanted or insertedinto the body of an animal, including humans. More particularly, theinvention relates to (but is not limited to) electro-optical-basedsensing devices for detecting the presence or concentration of ananalyte in a medium which are characterized by being totallyself-contained and of an extraordinarily compact size which permits thedevice to be implanted in humans for in situ detection of variousanalytes.

Description of Related Art

None of the references described or referred to herein are admitted tobe prior art to the claimed invention.

Implantable devices for monitoring various physiological conditions areknown. They include, for example, the sensors described in U.S. Pat. No.5,517,313 to Colvin; U.S. Pat. No. 5,910,661 to Colvin; U.S. Pat. No.5,917,605 to Colvin; U.S. Pat. No. 5,894,351 to Colvin; U.S. Pat. No.6,304,766 to Colvin; U.S. Pat. No. 6,344,360 to Colvin et al.; U.S. Pat.No. 6,330,464 to Colvin; U.S. Pat. No. 6,400,974 to Lesho; U.S. Pat. No.6,794,195 to Colvin; U.S. Pat. No. 7,135,342 to Colvin et al.; U.S. Pat.No. 6,940,590 to Colvin et al.; U.S. Pat. No. 6,800,451 to Daniloff etal.; U.S. Pat. No. 7,375,347 to Colvin et al.; U.S. Pat. No. 7,157,723to Colvin et al.; U.S. Pat. No. 7,308,292 to Colvin et al.; U.S. Pat.No. 7,190,445 to Colvin et al., U.S. Pat. No. 7,553,280 to Lesho; U.S.Pat. No. 7,800,078 to Colvin, Jr. et al.; U.S. Pat. No. 7,713,745 toColvin, Jr. et al.; U.S. Pat. No. 7,851,225 to Colvin, Jr. et al.; U.S.Pat. No. 7,939,832 to J. Colvin et al.; and in the following U.S. patentapplication Ser. No. 10/825,648 to Colvin et al. filed Apr. 16, 2004;Ser. No. 10/923,698 to Colvin et al. filed Aug. 24, 2004; Ser. No.11/447,980 to Waters et al. filed Jun. 7, 2006; Ser. No. 11/487,435 toMerical et al. filed Jul. 17, 2006; Ser. No. 11/925,272 to Colvin filedOct. 26, 2007; Ser. No. 12/508,727 to Colvin, Jr. et al. filed Jul. 24,2009; Ser. No. 12/493,478 to Lesho filed Jun. 29, 2009; Ser. No.12/764,389 to Colvin, Jr. et al. filed Apr. 21, 2010; Ser. No.12/966,693 to Colvin, Jr. et al. filed Dec. 13, 2010; Ser. No.13/103,561 to Colvin et al. filed May 9, 2011; and Ser. No. 13/171,711to J. Colvin et al. filed Jun. 29, 2011; the contents of all of theforegoing are incorporated by reference herein. Where terms used in thecurrent application are in conflict with use of the terms in theincorporated references, the definitions in the current application willbe controlling.

When a foreign object enters a body, there is an immediate immunologicalresponse (i.e., inflammation) to eliminate or neutralize that foreignobject. When the foreign object is an intentionally implanted material,device, or sensor, the inflammation response can cause damage to orotherwise negatively impact the functionality of the implant. Thus, aneed exists for an implantable device (or material) that can endure thebiochemical activity of an inflammation response and chronic foreignbody response, i.e. oxidation, such that the efficacy and useful life ofthe device is not adversely impacted. A corresponding need exists for amethod of manufacturing or treating an implantable device (or material)such that it can endure the biochemical activity of inflammation andforeign body response without significant loss of efficacy or usefullife.

The problem of in vivo oxidation and the corresponding in vivodestruction of materials and function by reactive oxygen species (ROS)associated with inflammation response is well known. As used herein, ROSstands for reactive oxygen species, highly reactive oxygen species, orreactive oxygen radical species, and includes peroxides such as hydrogenperoxide. Some means of at least partially protecting an implanteddevice or material from destructive oxidation have included the use ofantioxidants that may be either immobilized within or leached from animplanted device or material into the in vivo surrounding space.Systemic drugs such as anti-inflammatory varieties, superoxide dismutasemimetics, and other similar agents may also be leached or injectedlocally into the region around the implanted device or material incombination with, or alternatively to, antioxidants. In such cases, thedevice or material must either include or leach a drug or substance intothe local in vivo environment and thus can become influential on woundhealing, and causes the device itself to become a drug deliverymechanism in addition to its original intended purpose. Adding in theadditional drug/substance release features may add complexity,variability, and uncertainty into an implant design and may complicateproving the safety and efficacy of the device or material. Also, sincethe inflammation response is a normal part of healing that serves tokill any bacteria that may be in the wound, drugs or leached reagentswhich may disable this otherwise normal aspect of wound healing mightcompromise the patient. Ideally, an integrated device solution which canprotect just the susceptible and vulnerable component(s) of the implantwould be the safest and most efficient means of solving the problem.

SUMMARY OF THE INVENTION

Aspects of the invention are embodied, but not limited to, the variousforms of the invention described below.

In one aspect, the present invention relates to a device comprising animplantable device which has an in vivo functionality, as well as aprotective material in close proximity to the surface of the implantabledevice. The protective material prevents or reduces degradation orinterference of the implantable device due to inflammation reactionsand/or foreign body response. Further, the protective material cancomprise a metal or metal oxide which catalytically decomposes orinactivates in vivo reactive oxygen species or biological oxidizers.

In another aspect, the present invention relates to a device comprisingan implantable device which has an in vivo functionality as well as aprotective coating deposited on the surface of the implantable device.The protective coating prevents or reduces degradation or interferenceof the implantable device due to inflammation reactions and/or foreignbody response. Further, the protective coating can comprise a metal ormetal oxide which catalytically decomposes or inactivates in vivoreactive oxygen species or biological oxidizers.

In another aspect, the present invention relates to a method for usingan implantable device in in vivo applications. The method comprises atleast providing an implantable device which has an in vivofunctionality. The implantable device has a layer of a protectivecoating applied onto the device, wherein the protective coating appliedby the method prevents or reduces degradation or interference of theimplantable device due to inflammation reactions and/or foreign bodyresponse. The protective coating applied by the method can comprise ametal or metal oxide which catalytically decomposes or inactivates invivo reactive oxygen species or biological oxidizers. The method furthercomprises implanting the implantable device in a subject body.

In another aspect, the present invention relates to a method fordetecting the presence or concentration of an analyte in an in vivosample. The method comprises at least exposing the in vivo sample to adevice having a detectable quality that changes when the device isexposed to an analyte of interest. The device comprises in part a layerof a protective coating, wherein the protective coating prevents orreduces degradation or interference of the device from inflammationreactions and/or foreign body response. The protective coating cancomprise a metal or metal oxide which catalytically decomposes orinactivates in vivo reactive oxygen species or biological oxidizers,such that the device has enhanced resistance to degradation orinterference by oxidation as compared to a corresponding device withoutthe protective coating. The method further comprises measuring anychange in the detectable quality to thereby determine the presence orconcentration of an analyte of interest in the in vivo sample.

In another aspect, the present invention is an implantable glucosesensor for determining the presence or concentration of glucose in ananimal. The sensor can comprise a sensor body having an outer surfacesurrounding the sensor body, a radiation source in said sensor bodywhich emits radiation within said sensor body, an indicator element thatis affected by the presence or concentration of glucose in said animal,where the indicator element is positioned in close proximity to at leasta portion of the outer surface of the sensor body. Further, the sensorcan comprise a photosensitive element located in the sensor body,positioned to receive radiation within the sensor body, where thephotosensitive element is configured to emit a signal responsive toradiation received from an indicator element and which is indicative ofthe presence or concentration of glucose in an animal. Moreover, thesensor can comprise a protective barrier comprising silver, palladium,platinum, manganese, or alloys, or gold-inclusive alloys, orcombinations thereof, at least partially surrounding said indicatorelement.

In another aspect, the present invention can be a pacemaker comprisingan electrical generator, lead wires connected to said electricalgenerator, and a protective material in close proximity to or comprisingat least a surface of the pacemaker. The protective material can preventor reduce degradation or interference of the pacemaker due toinflammation reactions and/or foreign body response. Further, theprotective material can comprise a metal or metal oxide whichcatalytically decomposes or inactivates in vivo reactive oxygen speciesor biological oxidizers.

These and other features, aspects, and advantages of the presentinvention will become apparent to those skilled in the art afterconsidering the following detailed description, appended claims andaccompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is an illustration of the chemical reaction where an unprotected—B(OH)₂ recognition element of a glucose indicator is oxidized whenexposed to in vivo reactive oxygen species (ROS).

FIG. 1B is an illustration of the chemical reaction where a —B(OH)₂recognition element of a glucose indicator is not oxidized by in vivoreactive oxygen species (ROS) because the presence of silver, palladium,and/or platinum catalyzes the decomposition of hydrogen peroxide beforea —B(OH)₂ recognition element can be oxidized.

FIGS. 2A and 2B contain illustrations of examples of preferred indicatormonomers for use in combination with hydrophilic co-polymers inaccordance with embodiments of the present invention.

FIG. 3 is a graph showing loss of signal over time, due to reactiveoxygen species (ROS), from three glucose sensors which were not treatedaccording to an embodiment of the invention, following implantation in aliving body.

FIG. 4A is a picture of silver mesh used to deactivate hydrogen peroxidein accordance with an embodiment of the present invention.

FIGS. 4B and 4C are illustrations of designs for a mesh, according to anembodiment of the invention, that is configured to fit around animplantable sensor.

FIG. 5A is the absorption profile of four xylenol orange-based samplesused to test for the detection of hydrogen peroxide.

FIG. 5B is a comparison of the hydrogen peroxide production profile invivo with the profile of hydrogen peroxide degradation by silver.

FIGS. 6A and 6B are a side and cross-sectional illustration of anembodiment of the invention where a metal wire is wrapped in a coilaround a portion of an implantable sensor core.

FIGS. 6C and 6D are a side and cross-sectional illustration of anembodiment of the invention where a metal mesh is fitted around aportion of an implantable sensor core.

FIG. 6E is a side illustration of an embodiment of the invention where aslotted metal encasement is fitted around a portion of an implantablesensor core.

FIG. 6F is a side illustration of an embodiment of the invention where aperforated metal foil is fitted around a portion of an implantablesensor core.

FIG. 6G is a side illustration of an embodiment of the invention where aperforated metal jacket is fitted around a portion of an implantablesensor core.

FIG. 6H is a side illustration of an embodiment of the invention where ametal ring and a metal partial ring are fitted around a portion of animplantable sensor core.

FIG. 6I is a side illustration of an embodiment of the invention where ametal weave is in close proximity to a portion of an implantable sensorcore.

FIG. 6J is a side illustration of an embodiment of the invention where azig-zag patterned metal mesh is fitted around a portion of animplantable sensor core.

FIG. 7 is a representation of plasma sputtering of a metal onto theporous sensor graft of an implantable sensor.

FIGS. 8A, 8B, and 8C are cross-sectional scanning electron microscope(SEM) images, at increasing magnification levels, of metallic goldsputtered onto an implantable sensor core.

FIG. 9 is a SEM image of the outside surface of an implantable sensorcore sputtered with gold.

FIG. 10A is a diagram of a tortuous membrane of a porous sensor graft inaccordance with an embodiment of the present invention.

FIG. 10B is a diagram of a tortuous membrane, additionally showingindicator macromolecules dispersed throughout a porous sensor graft andsputter coated with a metal.

FIG. 11A is a general schematic of implant device showing animmobilization support for immobilizing indicator monomers in accordancewith an embodiment of the present invention.

FIG. 11B is a detail of FIG. 11A, further showing the immobilizationsupport, particularly the porous sensor graft membrane with indicatormonomers integrated into the graft and a platinum barrier layersputtered onto the surface of the porous sensor graft, and moregenerally, onto the device as a whole.

FIG. 12A is an illustration of a sensor core of an implantable sensorshowing a saddle cut on the sensor core with a tapered depth cut inaccordance with an embodiment of the present invention.

FIG. 12B is an illustration of a sensor core of an implantable sensorshowing a saddle cut on the sensor core with a uniform depth cut inaccordance with an embodiment of the present invention.

FIG. 12C is a design diagram of a saddle cut sensor core according to anembodiment of the invention.

FIG. 12D is a top view illustration of a uniform depth saddle cut sensorcore in accordance with an embodiment of the present invention.

FIG. 13 is an image of a saddle cut sensor core with indicatormacromolecule rehydrated on the surface.

FIG. 14 is an image of a 360 degree cut sensor core with indicatormacromolecule rehydrated on the surface.

FIG. 15 is an illustration of where on a saddle cut sensor core asputtered metal layer would be applied.

FIGS. 16A and 16B are images of a saddle cut sensor core with a platinumlayer sputtered on top of it.

FIG. 16C is an image of a saddle cut sensor core with a platinum layersputtered on top of it after the indicator macromolecules have beenexposed to buffer and rehydrated.

FIGS. 17A and 17B are graphical data relating to the modulation of lightintensity from sensor cores, both with and without layers of sputtercoated platinum, and the effect of the sputter coated platinum onexposure to hydrogen peroxide.

FIG. 18 is an illustration of a pacemaker that can be incorporated witha protective material according to an embodiment of the presentinvention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is embodied in an apparatus and/or material, andmethods of using such an apparatus and/or material, designed to beimplanted into a living body and to perform an in vivo functionality.Such a system may preferably comprise an implantable sensor, and morepreferably, an implantable glucose monitoring sensor. Such a sensor mayhave a smooth and rounded, oblong, oval, or elliptical shape (e.g., abean- or pharmaceutical capsule-shape). While the preferred embodimentof the device described herein is that of a glucose detection sensor,the present invention is not limited to only implantable glucosesensors, or only implantable sensors, or even limited to only sensors.

An object of the invention is to protect an implantable sensor,material, or device which may be either destroyed, weakened (in eithersignal or mechanical strength), or suffer diminished function or utilityas a result of oxidation from ROS typically due to inflammationreaction. Such diminished function or utility may be manifested as theloss of mechanical strength, pitting, leaching undesirable degradationproducts into the body, tissue damage from surface deformation, or theloss of kinetic profile of a drug delivery system. The inflammation isoften stimulated by the implantation procedure, the implanted device, orboth. A further object of the invention is to incorporate a featureincluded within the design of a sensor or other implantable device orcomponent (which device or component may be susceptible to damage byambient reactive oxygen species) that will protect the implanted sensoror device from oxidative damage or degradation. Highly reactive oxygenspecies (ROS) known to occur within living systems and cause damageinclude, for example, hydrogen peroxide (H₂O₂), hydroxyl radical (OH⁻),hypochlorite (OCl⁻), peroxynitrite (OONO⁻), and superoxide (O₂ ⁻). Ofthese ROS species, hydrogen peroxide appears to be the most problematicin causing damage to an implanted sensor or device in vivo. Thus, aspecific object of the invention is to protect the in vivo function of asensor or device from signal loss and shortened useful life due tohydrogen peroxide and other ROS produced within the body.

Certain metals such as silver, palladium, and platinum, and oxides ofthose and other metals, such as manganese, have a catalyticfunctionality that decomposes hydrogen peroxide into molecular oxygenand water. Thus, embodiments of the present invention seek to use suchmetals in conjunction with materials sensitive to oxidation to preventhydrogen peroxide from oxidizing the materials susceptible to oxidation.In particular, the material sensitive to oxidation may be indicatormacromolecules dispersed throughout a porous sensor graft according toembodiments of the invention. As used herein, “indicator macromolecule”refers to a structure comprising an indicator monomer co-polymerizedwith a relatively hydrophilic molecule or structure. In some embodimentsof the invention, the metals or metal oxides that catalyze thedecomposition of hydrogen peroxide are combined with materials sensitiveto oxidation by various configurations in close proximity to thesensitive materials, such as in the form of a wire, mesh, or coil atleast partially surrounding the material to be protected. In furtherembodiments of the invention, the metals that have a catalyticfunctionality may be alloys with other metals, such as gold, to takeadvantage of the properties of such other metals. In other embodimentsof the invention, the metals that catalyze the decomposition of hydrogenperoxide are combined with materials sensitive to oxidation by coatingareas in close proximity to the sensitive materials with metal or metaloxides via sputter deposition. In embodiments, a portion of the materialsensitive to oxidation may be coated with catalyst to provide protectionto the remaining adjacent portion. In embodiments, catalytic porous orROS diffusive contacting layers can be positioned between the ROS andthe species to be protected. Embodiments of the invention may act ascatalytic selective barriers or permselective diffusion barriers.

Hydrogen peroxide is considered the most problematic of the ROS thatdestroys implant functionality. The other four ROS species do not appearto have a significant effect on implant functionality as these speciesare either destroyed, not stimulated to production, or converted intoperoxide in vivo. The more reactive superoxide is converted to hydrogenperoxide naturally by superoxide dismutase. Hydroxyl radicals are soextremely reactive that they cannot diffuse very far before reactingwith something and are, therefore, limited in some embodiments to adistance on the scale of angstroms on the surface of an implanted deviceor material. Hypochlorite, in the presence of hydrogen peroxide, isdecomposed into water, oxygen, and a chloride ion. Nitric oxide (NO)radical, in the presence of superoxide in vivo, produces peroxynitritewhich is decomposed via ambient carbon dioxide which itself acts as adecomposition catalyst. Hydrogen peroxide is both reactive andsufficiently stable to have the persistence to diffuse throughout aporous sensor graft and indicator region of a sensor and oxidize allindicator molecules present, resulting in a loss of sensor function invivo.

Devices useful in the practice of the present invention include thosedescribed in the patents and publications listed above (para. [0004])and incorporated by reference herein. In a preferred embodiment, thedevice is an implantable glucose monitoring sensor such as the sensorsdescribed in U.S. Pat. No. 7,553,280, U.S. Pat. No. 7,800,078, or U.S.Pat. No. 7,713,745. In some embodiments of the present invention, thesensor may include a sensor body, a porous graft coated over, imbeddedwithin a pocket, or immobilized onto the exterior surface of the sensorbody. The sensor may also include fluorescent indicator monomersdistributed throughout and co-polymerized with the porous sensor graftmaterial that generate signal indicative of the level of fluorescence inthe indicator graft. The sensor may also include a radiation source(e.g. an LED), and a photosensitive detector element. An example of thisis disclosed in U.S. Pat. No. 7,553,280, which is incorporated herein byreference. The co-polymerized indicator monomers, which can be referredto as indicator macromolecules, are formulated to create a porous sensorgraft, with recognition monomers of the graft located throughout theporous co-polymer graft material. The sensor body, alternativelyreferred to as a sensor core, may be formed from a suitable, opticallytransmissive polymer material with a refractive index sufficientlydifferent from that of the medium in which the sensor will be used, suchthat the polymer can act as an optical wave guide. In one embodiment,the sensor may also have a power source to power the radiation source aswell as an active or a passive means of data telemetry that canwirelessly convey a signal, based on the photosensitive detector, to anexternal receiver. An example of this is disclosed in U.S. Pat. No.7,800,078, which is incorporated herein by reference. The sensor bodymay completely encapsulate the radiation source and photosensitivedetector, as well as other electronic equipment, creating aself-contained device. In some embodiments, the porous sensor graft andindicator macromolecules are only located within a certain region on thesurface of the sensor body.

In various embodiments of the invention, the specific composition of theporous sensor graft and the indicator monomers may vary depending on theparticular analyte the sensor is to be used to detect, and/or where thesensor is to be used to detect the analyte. Preferably, the poroussensor graft, which can comprise pores of varying size generallyreferred to as macro-pores or micro-pores, facilitates the exposure ofthe indicator macromolecules to the analyte, and the opticalcharacteristics of the indicator macromolecules (e.g., the level offluorescence of fluorescent indicator macromolecules) are a function ofthe concentration of the specific analyte to which the indicatormolecules are exposed. The pores of a sensor graft are generally ofsufficient size to allow for the diffusion of a specific analyte throughthe sensor graft. In a preferred embodiment, the porous membranestructure of the sensor graft, and the size of the macro-pores (about 1micron on average), creates a light scattering effect which provides anapproximate 78% increase in signal relative to a clear non-scatteringpolymer formulation. This light scattering increases the overallefficiency of the system and gives the graft a white appearance.

Fluorescent molecules may be used in diagnostics as tags and probes whenlinked to antibodies or other molecules, and can be configured at amolecular level to be used as chemical and biochemical active indicatorsspecifically designed to detect certain analytes, for example, glucose.Fluorescent sensors using an anthrylboronic acid-containing compound canbe used as a fluorescent chemosensor for signaling carbohydrate binding,including the binding of glucose and fructose. Fluorescent molecules aresusceptible to degradation, where they lose fluorescence intensity (orbrightness) over time by often variable rates of oxidation. Theoxidation may be commonly associated with photobleaching, (i.e.photo-oxidation), or with various reactive oxygen species within thelocal environment of the fluorescent molecule. Inside a living body,normal reactive oxygen species are potential oxidants and can includethose involved in typical healthy healing reactions such as hydrogenperoxide, hydroxyl radicals, peroxynitrite, superoxide, and others.Inside a living system there are also specific enzymes called oxygenasesfor the specific purpose of oxidation in the breakdown of molecules. Anadverse result of reactive oxygen species or oxygenase activity on afluorescent molecule is typically loss of fluorescence. In the case ofan indicator molecule, or a passive tag, probe, or label, the usefullife and sensitivity of the device, or diagnostic, is limited, or may berendered completely ineffective by oxidative degradation of fluorescentsignal.

A source of ROS in the interstitial fluid (ISF) may be from neutrophils,which are not normally within ISF except when responding to injury.Neutrophils are typically within the interstitial space for a limitedamount of time in response to injury in order to conduct theirparticular repair and protection functions. Neutrophils release highlyreactive oxygen species which serve to oxidize and break down anydamaged tissue and any foreign material to permit theregeneration/repair to complete. As seen in FIG. 1A, these reactiveoxygen species can also damage the implanted device, material, or sensorby attacking key functional components such as materials and/or chemicalindicators that may be susceptible to oxidation.

Preferred indicator monomers used in embodiments of the inventioninclude those described in U.S. Patent Application Publication No.2007/0014726 which are designed to be resistant to oxidation damage fromreactive oxygen species. However, one of ordinary skill would recognizethat many types of indicators may be used, particularly those describedin the patents and publications referred to above (para. [0004]). In apreferred embodiment, the indicator comprises a phenylboronic acidresidue.

Preferred indicator monomers used in embodiments of the invention mayalso include those described in U.S. Pat. No. 7,851,225 which aredesigned to include an electron withdrawing group in order to reduce thesusceptibility to oxidation of the indicator molecules. In embodimentsof the invention, indicator molecules containing an aryl boronic acidresidue may be made more resistant to oxidation by adding one or moreelectron-withdrawing groups to the aromatic moiety which contains theboronic acid residue, thus stabilizing the boronate moiety. It will beunderstood that the term “aryl” encompasses a wide range of aromaticgroups, such as phenyl, polynuclear aromatics, heteroaromatics,polynuclear heteroaromatics, etc. Non-limiting examples include phenyl,naphthyl, anthryl, pyridyl, etc. A wide range of electron-withdrawinggroups is within the scope of the invention, and includes, but is notlimited to, halogen, cyano, nitro, halo substituted alkyl, carboxylicacid, ester, sulfonic acid, ketone, aldehyde, sulfonamide, sulfone,sulfonyl, sulfoxide, halo-substituted sulfone, halo-substituted alkoxy,halo-substituted ketone, amide, etc., or combinations thereof. Mostpreferably, the electron withdrawing group is trifluoromethyl. Inembodiments of the invention, the electron withdrawing groups of theindicator molecules occupy the R₁ and/or R₂ positions in either of thespecific chemical structures of the indicator molecules shown below:

wherein each “Ar” is an aryl group; each R1 and R2 are the same ordifferent and are an electron withdrawing group; “m” and “n” are eachindependently integers from 1 to 10; R4 is a detectable moiety; and eachR is independently a linking group having from zero to ten contiguous orbranched carbon and/or heteroatoms, with at least one R furthercontaining a polymerizable monomeric unit. In a particularly preferredembodiment, the indicator comprises one or more of the compoundsdepicted in FIGS. 2A and 2B. It will also be understood from the abovedefinition that the indicator monomer compounds and detection systemsmay be in polymeric form.

It should be understood that the invention described herein can protectany indicator, and is not limited to the preferred structures detailedin FIGS. 2A and 2B. Other materials and biologics that are put into abody may also be damaged by oxidation, particularly from oxidation dueto ROS. Such other materials could be absorbance type indicators,proteins, molecules, orthopedic implants, cosmetic implants, pacemakerwires, etc. As long as the indicator or structure is susceptible tooxidation by peroxides/ROS, the invention described herein will protectsuch indicators or structures.

An implantable device requires a breach of the skin of some size simplyto permit insertion of the device. In one embodiment of the presentinvention, a sensor is implanted through the skin in a procedure toplace it within the subcutaneous space between muscle and dermis.Mechanical damage occurs to local and adjacent tissue as a result of theforeign body intrusion, even for the smallest and most biocompatibledevices. This is because one must first penetrate the skin, and thenmust displace tissue to create a pocket or space where the device willbe deposited and remain in place to execute its intended in vivofunction. The relative biocompatibility of the sensor itself, other thanits relative size and displacement, does not influence the minimaldamage that is imposed on localized tissue in order to put the sensor ordevice into place. As a result of foreign body intrusion and localizedtissue damage, an immediate and normal inflammation cascade commenceswithin the host in direct response to the intrusion for the purpose ofprotecting the host, and immediately begins a repair process to correctthe mechanical damage of intrusion, i.e. the wound begins to heal.

It is observed that when a sensor is placed into an animal, and evenmore acutely within a human, there is a near immediate biologicalresponse, and a damage inflicted on the extended performance of thesensor by the body as a direct result of inflammation. The net result ofthe damage from inflammation reaction is to shorten the useful life ofthe device, for example by diminishing signal strength. For otherdevices, the reduction in useful life could be measured in terms ofresponse fouling, reducing mechanical strength, electrical or mechanicalinsulation properties, surface erosion (which can affectbiocompatibility), or according to other measurable properties.

Inflammation response is composed in part by a transient conditionoccurring in direct response to an injury. There is necessarily a minortissue injury as a result of implanting a device and it has beenobserved that particular aspects of the inflammation response associatedwith ROS can negatively affect an implanted device. Further, after thetransient period of healing, although the inflammation conditionsurrounding the sensor significantly subsides, there is a chroniclow-level foreign body response to an implanted device.

A solution to the above-referenced problems is to apply a material,structure, and/or a coating on or around the surface of the implanteddevice that decomposes the ROS generated locally in the region of theimplant. Once a device is implanted, the material, structure, and/orcoating provides a chemical barrier against ROS entering the poroussensor graft, thus preventing where ROS can attack the indicator systemvia oxidation, as illustrated in FIG. 1B.

In embodiments of the invention, the material, structure, and/or coatingmay include physiologically compatible metals or metal oxides that arecapable of catalyzing the decomposition of ROS (particularly hydrogenperoxide), such as, for example, silver, palladium or platinum, or theiroxides, that are sufficiently non-toxic within an in vivo environment.When the physiologically compatible metals are embodied as a coating inembodiments of the present invention, the coating may be applied to thesensor material in any suitable fashion, such as by sputter deposition.The thickness of the material, structure, and/or coating can varywidely, for example, from about 0.5 nm to about 2.5 mm. In furtherembodiments of the invention, the thickness of the material, structure,and/or coating can be from about 1 nm to about 20 nm thick. In yetfurther embodiments of the invention, the thickness of the material,structure, and/or coating can be from about 3 nm to about 6 nm thick.

FIG. 3 is a graph illustrating an example of normalized signal loss as aresult of biological response to device implantation, particularly thepresence of ROS, where the signal is from implanted glucose sensors. Thedata in FIG. 3 were obtained from three sensors, implanted into threedifferent humans (identified as P06, P10, and P11), within thesubcutaneous space in the dorsal wrist area. Following the completion ofthe procedure, an external watch reader was placed over the sensor toallow data communication between the sensor and external reader. Signaldata were taken from the sensor over four days. It can be seen from FIG.3 that a very rapid and significant signal drop occurs within the firstday following the implant procedure (the procedure itself requiresapproximately 5 minutes). On the normalized scale, the signal in two ofthe sensors dropped by effectively 100% after twenty-four hours whilethe signal from the third sensor dropped by about 90% after twenty-fourhours. This signal drop is undesirable because it shortens the overalluseful life of the implant.

Embodiments of the present invention address the oxidation mechanism bywhich the ROS associated with inflammation reaction can damage a sensorimplant placed within the interstitial space or anywhere that ROS may bepresent. Particularly, embodiments of the invention address the loss ofsignal by oxidation of indicator macromolecules, where the oxidation iscaused by ROS. Analysis of sensors explanted from humans (and animals)shows specific and definitive evidence of reactive oxygen speciesattack. In the context of the present invention, an explanted sensor isa sensor (or generally any foreign object which is not biologicaltissue) which has been implanted into a living body and subsequentlyremoved from that body. An explanted sensor may possess biologicalmaterial that remains attached to the explant after extraction from theliving body. The oxidants potentially associated with wound healinginclude hydrogen peroxide, superoxide, hypochlorite, peroxynitrite, andhydroxy radical as produced from local repair cells migrated to the sitein response to injury. The specific oxidation reaction damage from ROSinflicted on the indicator macromolecule, which in embodiments of theinvention operates as a glucose sensor, is shown in FIG. 1A.

FIG. 1A represents the in vivo ROS oxidative deboronation reaction ofone glucose indicator molecule (monomer) that may be useful inconnection with the present invention, and shows that as a direct resultof ROS produced by the neutrophil repair cell mechanism, the boronaterecognition element of the indicator system is converted to a hydroxylgroup. The conversion of the standard indicator molecule to the in vivoaltered indicator molecule, where the boronate recognition element ofthe indicator system had been oxidized to a hydroxyl group, causes atotal loss of activity (specifically, fluorescence modulation asaffected by glucose concentration) in the molecule. The critical bondenergies in the reaction as shown in FIG. 1A are: C—C=358 kJ/mol;C—B=323 kJ/mol; and B—O=519 kJ/mol. These bond energies indicate thatthe carbon-boron bond, having the lowest bond energy, is most readilysusceptible to attack and cleavage by oxidation. This analysis isconfirmed by an Alizarin Red assay (negative for boronate), andadditionally from a Gibbs test (positive for phenol) on an explantedsensor from extended animal testing. The loss of boronate from theindicator molecule directly results in loss of fluorescent signalmodulation.

As stated above, ROS driven oxidation is a result of normal healinginflammation resulting from the stimulus of implanting the sensor underthe skin and the attendant disruption and small damage to localizedtissue. When the indicator macromolecule includes one or more boronicacid recognition elements, ROS driven oxidation causes deboronation,resulting in a loss of signal from the indicator macromolecule, therebyshortening the useful life of a sensor. ROS driven oxidation may alsoshorten the useful life of other similarly susceptible devices ormaterials. Hydrogen peroxide has been identified as the most likely ROSspecies that oxidizes the indicator macromolecule of the implant.

However, the decomposition of hydrogen peroxide into oxygen and water iscatalyzed by metallic silver as follows:

Experiments, as described below, were conducted to determine howmetallic silver could be installed or configured onto or within a sensoraccording to an embodiment of the invention in such a way as to protectthe indicator graft by decomposing hydrogen peroxide faster than theperoxide could destroy the in vivo functionality of the sensor.Additionally, other metals, including palladium and platinum, werestudied for similar activity against hydrogen peroxide and incorporationwith a sensor according to an embodiment of the invention. FIG. 1Brepresents the in vivo protection of one glucose indicator molecule thatmay be useful in connection with the present invention from ROS drivenoxidative deboronation reaction due to the presence of metals thatcatalyze the decomposition of hydrogen peroxide in accordance withembodiments of the present invention. Further, oxides of metals thatcatalytically decompose hydrogen peroxide may be suitable forembodiments of the invention.

An embodiment of the invention is an implantable device that includes aprotective layer which protects the device from the effects of ROSdriven oxidation. In embodiments, the device can be a sensor at leastpartially encased with a porous sensor graft, where the porous sensorgraft can have indicator macromolecules embedded within the graft thatare sensitive to an analyte of interest. In preferred embodiments, theindicator macromolecules can be sensitive to the presence of glucose. Inembodiments, the protective layer is comprised of a metal that catalyzesthe breakdown of ROS before ROS can react with any other components ofthe implantable device. In some embodiments, the metal of the protectivelayer is comprised of silver, platinum, palladium, manganese, and/oralloys or gold-inclusive alloys thereof. In some embodiments, theprotective layer can be in the form of a wire, mesh, or other structuralencasement wrapped around at least a part of the device. In otherembodiments, the protective layer can be in the form of a coatingsputter-deposited on at least a part of the device. These non-limitingembodiments are used as exemplary embodiments as set forth below.

In one embodiment of the invention, metallic silver is placed betweenthe sensor graft and an external environment such that any hydrogenperoxide would be required to diffuse through a porous catalyticbarrier, such as a mesh, and thus be decomposed into water and oxygenprior to any reaction with the indicator molecules. The efficacy ofsilver for decomposing hydrogen peroxide was tested using 180×180 micronpure silver mesh, as seen in FIG. 4A. (The value used for the meshrefers to wires/inch. FIG. 4A also shows a 25 micron thick (diameter)gold wire along with the silver mesh to provide scale.) FIG. 4B is anillustration of a mesh 403 and how a mesh 403 would fit around thesensor 401, wherein the sensor 401 has a region of porous sensor graft402, according to an embodiment of the invention. FIG. 4C is a furtherillustration of a side and end views of a mesh used in accordance withan embodiment of the invention.

To test the catalytic effect of a silver mesh on hydrogen peroxide, foursamples (Samples A, B, C, and D) containing xylenol orange were testedas set forth below. The detection is based on the oxidation of ferrousto ferric ion in the presence of xylenol orange, where a sample thatdoes not contain hydrogen peroxide in solution appears clear and orange.When hydrogen peroxide is present in combination with xylenol orange,the solution appears purple and opaque. Sample (A) was a control whichhad no hydrogen peroxide added. Sample (B) contained 0.2 mM hydrogenperoxide without any silver present; the hydrogen peroxide in the samplecaused the solution to be purple and opaque. Sample (C) contained 0.2 mMhydrogen peroxide with silver mesh present for thirty (30) minutes.Compared to sample (B), sample (C) was more clear and lighter in color,indicating that the amount of hydrogen peroxide in the solution ofsample (C) was decreased. Sample (D) contained 0.2 mM hydrogen peroxidewith silver mesh present for sixty (60) minutes. Sample (D) was orangein color and clear and appeared identical to Sample (A), the control,indicating that there was no hydrogen peroxide remaining in the solutionof Sample (D).

FIG. 5A shows the absorption profile across the spectrum of visiblelight for Samples (A), (B), (C), and (D). Notably, the absorptionprofile of sample (D), 0.2 mM hydrogen peroxide exposed to silver forsixty (60) minutes, is nearly identical to the absorption profile of thecontrol sample (A) which contained no hydrogen peroxide.

FIG. 5B shows a comparison between the in vitro decomposition profile ofhydrogen peroxide by silver mesh in water and the in vivo productionprofile of hydrogen peroxide as measured in a human body implant site.The in vitro decomposition profile is of an about 60 mg silver mesh in1.5 mL of 0.2 mM hydrogen peroxide in water at a pH of about 7. Incomparing the two profiles, it is evident that the rate of hydrogenperoxide decomposition using a silver catalyst, such as the 180×180 puresilver mesh, is approximately seven times faster than the in vivo rateof hydrogen peroxide production, as measured in human type 1 diabeticwound healing.

The catalytic activity of silver in decomposing hydrogen peroxide intowater and oxygen is so effective, that any silver used for this purposein combination with an implantable device would still be effective evenif only in close proximity to the implant. In other words, silver doesnot necessarily need to be bonded to or incorporated with the structureof the device. However, it is known that the in vitro catalytic activityof silver degrading hydrogen peroxide can be inhibited by chloride ions.This inhibition of silver by chloride can be referred to as silvercatalyst poisoning.

Other metals, such as palladium and platinum, also decompose hydrogenperoxide at different rates and efficiencies and kinetic profiles. Theinventors of the present invention have found that neither palladium norplatinum was poisoned by chloride or inhibited by high proteinconcentrations of serum albumin (70 mg/ml or greater). Similarly tosilver, palladium and platinum also decompose hydrogen peroxide at arate faster than the body can produce hydrogen peroxide and areeffective, in close proximity to an implantable device, at preventinghydrogen peroxide from reaching and/or damaging the device.Alternatively, alloys of silver, palladium, platinum, gold orcombinations or oxides thereof may be used to catalyze the degradationof hydrogen peroxide into oxygen and water. Close proximity, in thecontext of the present invention, is a distance close enough to allow adevice and/or material to function in the intended manner. The range ofdistance or thickness that qualifies as in close proximity will vary,depending on the structure and configuration of the structuralembodiment. Typically, the range of close proximity will be up to about2.5 millimeters. In embodiments of the invention, the structure used toprotect the sensor does not have to completely surround or encapsulatethe sensor body, but only needs to be implemented to protect theindicator region of the sensor.

Samples of platinum and palladium were separately placed in solutions of0.2 mM hydrogen peroxide at 37° C. in phosphate buffered saline (PBS)for several hours. The samples were platinum meshes and palladium coilswrapped from pure metal wire and slid over the membrane graft region ofa sensor core according to an embodiment of the invention. Thisexperiment was repeated with many different samples, with fresh hydrogenperoxide introduced in each trial. The platinum and palladium samplescompletely degraded the hydrogen peroxide in solution. In someembodiments of the invention, platinum and palladium are preferredmetals to use in designing structures that incorporate a metal catalystinto the sensor. Such structures can be up to about 2.5 mm in thickness,measured from the surface of a device.

FIGS. 6A and 6B illustrate a side and cross-sectional view of a wire 602wound around a sensor core 601 in accordance with embodiments of theinvention. FIGS. 6C and 6D illustrate a mesh 603 wound around a sensorcore 601 in accordance with embodiments of the invention. Innon-limiting embodiments, the wire and mesh are wrapped into coil orcylinder configurations and slipped over the sensor such that analytes,such as glucose, could diffuse between the cracks of the coils or mesh.Other structural configurations contemplated for embodiments of theinvention, in addition to metal or metal oxide in a coil or mesh form,are as a perforated or slotted encasement 604 as in FIG. 6E, aperforated or slotted foil 605 as in FIG. 6F, a perforated or slottedjacket 606 as in FIG. 6G, a ring or partial ring 607 as in FIG. 6H, aweave or Dutch weave 608 as in FIG. 6I, a zig-zag patterned mesh 609 asin FIG. 6J, and other such structures made from either metal and/ormetal oxide wire and/or ribbon, or other forms of material stock. Thesestructures are designed such that hydrogen peroxide in the environmentwill react on the metal as the hydrogen peroxide tries to diffuse intothe graft of the implantable sensor. In preferred embodiments of theinvention, designs are intended to both increase the surface area of themetal exposed to the external environment and to be a diffusion layerwith a sufficient density of pores, gaps, and/or perforations coveringthe surface of the graft of an implantable sensor, so as to protect thegraft indicator macromolecules from oxidation by ambient hydrogenperoxide.

An alternative embodiment of the invention may use nanoparticulate formsof metals that catalyze the degradation of hydrogen peroxide (asdisclosed herein), suspended within a porous sensor graft. In onenon-limiting embodiment, formation of a porous sensor graft material mayinvolve a gel suspension, to which nanoparticulate metals can be added.Once formed as part of a device, the porous sensor graft withnanoparticulate metals entrapped within the graft can operate to preventROS driven oxidation of other components of the sensor graft and device,such as indicator molecules. In embodiments of the invention, thenanoparticulate metals can be distributed evenly throughout the poroussensor graft and/or micro-localized within the graft. In an non-limitingembodiment of the invention, the nanoparticulate metals may be up to 80nm in diameter.

While embodiments utilizing structural encasements (e.g. wire, mesh,sheath, etc.) are successful at protecting implantable devices fromoxidative degradation by hydrogen peroxide, because of the very smallsize of implantable devices, it is recognized that such protectivestructures may be awkward or difficult to mechanically install onto suchdevices as a barrier between the graft and outside solutions (andtissue). The use of such structural encasings may also have a high cost,especially in the case of platinum and palladium materials. Edgeeffects, surface morphology, and fabrication quality at the smalldimensions required for structures to be incorporated with animplantable device may also be issues with structural encasings.Additionally, catalysis of hydrogen peroxide occurs on the surface ofthe metal and, relative to the size of a hydrogen peroxide atom, theamounts of metal contemplated in structural embodiments may be orders ofmagnitude greater than might be theoretically required to achieve thedesired decomposition of hydrogen peroxide. It is also a concern thattissue may also grow into the spaces of a coil, mesh, weave, etc. andmake any potential removal of the sensor more tedious and damaging tolocal tissue to some extent. This does not mean to imply, however, thatembodiments utilizing structural encasements are not viable and robustsolutions to the above-described problems relating to ROS drivenoxidation. To the contrary, they have been shown to be very effective.

In other embodiments of the invention, the protective metals may beapplied to the porous sensor graft using sputter coating techniques. Forexample, the techniques can use sputtering targets comprising silver,platinum, palladium, manganese, gold, and alloys and/or oxides thereof.A sensor graft sputter coated with metal or metal oxide must remainsufficiently porous to allow analytes to pass through into the sensorgraft, but still effectively work as a protective barrier against thediffusion of hydrogen peroxide into the sensor graft. In embodiments ofthe invention, the metal or metal oxide acting as a catalyst may beconfigured as a slightly tortuous diffusion layer between outside worldand inner graft, which protects the indicator from hydrogen peroxideeven at high concentrations and fast physiological production rates. Theslightly tortuous diffusion layer may also be characterized as apermanently selective catalytic barrier.

Sputter deposition is a well-known method of depositing thin metal filmsby sputtering, i.e. ejecting, material from a metal source or “target,”after which the atoms from the target deposit onto a substrate.Typically, within a vacuum sealed environment, high energy ionized gasesform a plasma and are projected at a target which causes atoms of themetal target to be broken off from the target. As the metal atomsdislodged from the target deposit onto a substrate, a thin film of thatmetal forms on and bonds to the substrate. Depending on the gas used forprojection onto the target and the composition of the target itself, themetal film that is deposited on to the substrate may be a pure metal, analloy, an oxide, a nitride, an oxynitride, etc. FIG. 7 is a generalrepresentation of a sputter coating chamber.

A gold target was used for the initial testing of sputter depositiononto a porous sensor graft. FIGS. 8A-C are three SEM images, increasingin magnification, of the sensor graft sputter coated with gold. Theporous sensor graft material itself is normally not visible by SEM. Theimages in the photos are of metallic gold, which is visible under SEM,sputtered onto the surface of the hydroxyethylmethacrylate (HEMA)copolymer graft 801. Thus, these photos are only of the metallic goldshell covering the graft element surface following sputter depositionusing a gold target. The sensor graft 801 used for FIGS. 8A-C wascleaved and then sputtered, such that the cross-sectional image and fulldepth of the graft membrane could be observed under SEM. If sputteredfrom outside only, then cleaved, then SEM imaged, the expected imagewould be a metallic porous thin layer riding atop an invisible organicgraft layer below. The metallic gold layer visible in the graft regionis very thin (a few nm), with a very high surface area, at leastmatching that of the porous graft itself. Sputter coating the graft 801with metal does not clog or foul the macro-porosity of the graft; i.e.analytes of interest will still be able to diffuse through and interactwith indicator molecules. In embodiments of the invention, the coatingused to protect the sensor does not have to completely surround orencapsulate the sensor body 802, or even cover the entire portion ofporous graft 801 present on a sensor, but only needs to be implementedto protect the indicator region of the sensor.

FIG. 9 is an SEM photo from the outside surface of the graft lookinginward toward the sensor body. Again, this image is not technically ofthe graft, but is rather an image of metallic gold sputtered over thegraft, which allows the graft to be visualized by SEM. This image showsthat effectively the entire surface area of the graft visible is coatedwith gold. Thus, it can be inferred that the surface area of exposedmetal at least is equivalent to the surface area of the graft. Anembodiment as described above in FIG. 6A used a 400 micron diameterpalladium wire coil wrapped around the outside diameter and displayedexcellent protection against hydrogen peroxide. The sputter coating ofmetal onto the porous sensor graft has a surface area greater than thewire coil. This implies that the protective ability of sputter coatedmetal on a porous sensor graft may be superior to embodiments utilizinga structural encasement of the invention discussed above.

FIG. 10A is a representation of the tortuous membrane structure 1000that comprises the porous sensor graft, which can be a portion of anouter structure of a sensor body 1003, in accordance with an embodimentof the invention. Any solute 1001 must follow a tortuous diffusion path1002 to pass through and cross the membrane 1000. FIG. 10B is arepresentation of the tortuous membrane 1000 with a metalized surfacelayer 1004, with indicator molecules 1005 also represented in the poroussensor graft 1000. Although this creates a tortuous diffusion barrier,the macro-pores are still about 1 micron, and wide open without metalfouling. In embodiments, the depth of the porous sensor graft sputteredis limited to line of sight at the micro level. Metal sputtered from atarget generally cannot diffuse deep into the tortuous membranestructure because the sputtered metal deposits upon impact, and thusareas below the surface that are shadowed remain uncoated, asrepresented in FIG. 10B. In some embodiments of the invention, thethickness of this metalized layer 1004 into the porous sensor graft maybe 5 microns or less. In other embodiments, additional pressure may beintroduced to the sputtering environment, magnetic fields may be used,or other methods may be used to cause the tortuous membrane 1000 to besputtered past the point of line of sight deposition, such that themetalized layer 1004 may extend down through the full depth of theporous sensor graft. As stated above, the sensor graft remains porousafter sputter deposition.

In certain embodiments of the invention, the full depth of the poroussensor graft is about 100 microns. The surface area of the porous sensorgraft sputter coated with metal is expected to lose the function of anyindicator molecules covered by the sputtered metal. However, in such anembodiment, if about the top 5 microns are allocated to surfacemetallization to provide a catalytic metal protection layer, theremaining about 95 microns of sensor graft are more than adequate toprovide signal and modulation according to embodiments of the invention.There is no concern that the metal sputtered onto the graft membranewill have any negative effect on the structural integrity or function ofthe graft membrane. In embodiments of the invention, the thickness ofthe metal layer can be from about 0.5 nm to about 500 nm thick. In aparticular embodiment of the invention, the thickness of the sputteredmetal layer is about 1-20 nm thick. In a preferred embodiment of theinvention, the thickness of the sputtered metal layer is about 3-6 nmthick.

For preferred embodiments, both palladium and platinum are generallyused and commercially available sputtering targets. Either of thesemetals, or alloys or combinations of these metals or optionally othersof the type, can be used to sputter the surface of a porous graft layer.These metals, sputtered onto an sensor graft, can construct a protectivelayer over the graft that will permit free diffusion of glucose (orother analytes of interest), but will also decompose hydrogen peroxideencountered at the sensor surface during wound healing and for theduration of the useful life of the sensor in vivo. In variousembodiments, the entire surface of a sensor core can be sputter coatedor only a portion of the sensor core can be coated.

FIGS. 11A and 11B illustrate a representative sensor device that may beused in the context of the present invention. In particular, FIGS. 11Aand 11B show a polymer encasement 1103 containing microelectronics 1105in the interior 1104 of a representative electro-optical sensing device.The microelectronics 1105 may comprise microelectronic components suchas, for example, a radiation source 1102 and a detector 1101. In onepreferred embodiment, radiation source 1102 is an LED, although otherradiation sources may be used. Also in one preferred embodiment,detector 1101 is a photosensitive element (e.g. a photodetector,photodiode), although other detecting devices may be used.Microelectronics that may be contained in a representativeelectro-optical sensing device are described in U.S. Pat. No. 6,330,464,which is incorporated by reference herein in its entirety.

As shown in more detail in FIG. 11B, the surface of the sensor devicecomprises a tortuous membrane with a platinum metal coating 1004covering a porous sensor graft 1000, as similarly seen in FIG. 10B.

Metals within the scope of the invention (e.g. platinum, palladium,etc.) used as sputter coatings do not cause concern for potentialclogging or fouling of the pores of the sensor graft. For example, theatomic radius of a platinum atom is 135 pm, with a diameter of 270 pm,i.e. a platinum atom has a diameter of 0.27 nm. Thus, a sputter coatingof platinum that is about 3 nm thick, on top of the sensor graftsurface, would be about 11 platinum atoms thick. Similarly, an about 6nm thick platinum coating would be about 22 platinum atoms thick. So, anarrowing of a 1 μm (1,000 nm) wide macro-pore by the thickness of ametal coating on the pore wall by 6 nm would leave a pore diameter of994 nm, which is not a significant constriction of the pore. Similarly,with a gold sputter coating, the largest diameter of the macro-pores ofthe porous sensor graft as seen in the SEM image of FIG. 9 is about 1μm.

Because the sputter coating process disclosed does not completely fillin the macro-pores of a porous sensor graft, but rather lines theexterior macro-pores, some embodiments of the invention can retain theadvantages of an intentionally porous structure. Alternatively,non-porous structures can be sputter coated to achieve the same goal ofpreventing degradation by ROS. Sputter deposited catalytic coatings thathave a relatively fast rate of oxidizer degradation may alternatively oralso be applied adjacent to oxidation sensitive materials, such as theporous sensor graft in embodiments of the present invention, andeffectively prevent oxidative degradation of those oxidation sensitivematerials. For example, for a sensor (or other device) that has anoxidation sensitive region on only one half or less of the sensor, or ona part of its surface, a sputter coating can be applied to the oppositeside (i.e. back side) of that sensor (similar to the structuralencasement embodiment seen in FIG. 6H), and the proximity of the coatingcan be sufficient to protect the functional elements of the sensor fromoxidation, due to the fast kinetic degradation rate of ROS. Thesputtered coating does not have to be continuous; it can be applied asone or more regions of sufficient area, proximity, and/or shape asneeded to provide the amount (in terms of area and/or mass) of catalystto achieve the needed rate of oxidizer decomposition to protect thedevice, sensor, or material. Alternatively, the desired coating ofsputtered material could be made by simply masking the sensor or devicesurface before putting it into the sputter chamber, allowing for thedeposition of sputtered catalytic material according to the shape andplacement of catalyst desired.

For testing purposes, sputter coating was conducted with a platinumtarget resulting in a platinum coating on a sensor core (a sensor bodyaccording to an embodiment of the invention without the internal powersource, transmitter, etc.). In terms of weight, the total amount ofplatinum sputtered onto the porous sensor graft surface is expected tobe approximately 10 μg. This determination is made from sensor coresurface area estimation, metal density, and nominal metallizationthickness (about 3 nm). The corresponding weight of palladium isapproximately 5 μg for the same metallization thickness.

In order to efficiently sputter coat the porous sensor grafts,embodiments of the sensor cores were modified to have a “saddle cut”along part of the sensor core length. In some embodiments, this saddlecut is a recessed, uniform depth, pocket that is machined into thesurface of the sensor body that allows for the co-polymerizationfabrication of the indicator monomers with the porous sensor graftmaterial to be cast in that pocket region of the sensor body. Inembodiments, the porous sensor grafts with indicator macromolecules arelocated within these regions. The saddle cut localizes the area ofporous sensor graft with indicator macromolecules, and thus the area forsputter coating, which helps to minimize any parasitic interference withinductive power telemetry from the sensor when functioning in vivo.Further, the saddle cut allows for efficient setup of the sensor in asputter chamber, removing the need for rotation of the sensor corebecause only a localized area requires coating. In other embodiments ofthe invention, more than one side or region of the sensor core can besputter coated. In yet further embodiments of the invention, the coatingarea can have suitable shapes, such as, for example, round, square,rectangular, or even a region that continually surrounds the sensorcore, so long as the dimensions and geometry of the sputter coatingaccommodates the function of the sensor.

Embodiments of the inventions are further shown and illustrated in FIGS.12-16. FIG. 12A illustrates a side profile image of the saddle cut witha tapered depth cut. 12B illustrates a side profile image of the saddlecut with a uniform depth cut. FIG. 12C is a design schematic for thesaddle cut sensor core. FIG. 12D is an illustration of a top view of auniform depth saddle cut sensor core. FIGS. 13 and 14 show thedifference between a saddle cut sensor core (FIG. 13) and the standard“360 degree cut” sensor core (FIG. 14). The sensor core in FIGS. 13 and14 have been submersed in buffer, and the region with rehydratedindicator macromolecules is seen as opaque and white. As seen in FIG.14, a saddle cut graft is not required for all embodiments of thepresent invention; the porous sensor graft may be protected whether itis located in a specific region of a sensor body or completely coveringa sensor body. FIG. 15 is a further illustration of where a saddle cutsensor core would be exposed to sputtering (as illustrated, the lefthalf of a sensor core having a porous sensor graft region) in order toprotect the region of porous sensor graft with indicator molecules.

Other configurations or cuts may be used if manufacturing considerationsor in vivo functionality are enhanced by such configurations. Forexample, the sensor cores may be cut according to other geometries, haveperforations of a various depths that can be sputtered, or be surroundedby a film (that can be applied to any shape of device) that has beensputtered separately from the sensor core.

FIGS. 16A and 16B are images that show a saddle cut core with dried,indicator layers (porous sensor graft) which has been sputtered with 3nm of platinum, deposited with argon plasma. There is no visibleevidence of the platinum coating because the layer is so thin. Uponsubmersion in buffer, the clear dried (sputtered) graft is rehydrated tothe white opaque functional state as shown in FIG. 16C. No evidence ofthe surface metallization is visible because the metallization layer at3 nm is only about 11 atoms thick.

FIGS. 17A and 17B present modulation data of signal intensity from threesensor cores (in terms of percentage of modulation and absolutemodulation, respectively). Modulation refers to the signal intensitymeasured from the sensor cores. Three saddle cut cores were tested, onecontrol that did not undergo sputter coating, and “core 2” and “core 3”which were sputtered with platinum at two different thicknesses, wherecore 3 had a thicker platinum layer than core 2.

Before the hydrogen peroxide treatment, each core was measured with afluorometer for signal intensity in the presence of 0 mM glucose and 18mM glucose. Next, each core was submerged in 0.2 mM hydrogen peroxide inbuffer at 37° C. for 24 hours then tested again for signal intensity.The signal intensity of the unprotected core was destroyed within onlyone 24 hour treatment with hydrogen peroxide. Core 2 and core 3 remainedunaffected (within experimental error). The system was reloaded for core2 and core 3 for a second 24 hour hydrogen peroxide exposure session.After the second oxidation, a total of 48 cumulative hours of hydrogenperoxide exposure, neither core 2 nor core 3 showed significantdegradation due to hydrogen peroxide. The data for core 3 with a thickerplatinum layer on the surface appears slightly better (more protected),although this may be experimental error in the spectrometer setup or theresult of a very small sampling.

FIGS. 17A and 17B show that after 24 hours of submersion in 0.2 mMhydrogen peroxide, the control sample core which was not sputter coatedwith platinum had its signal destroyed by hydrogen peroxide exposure. Incontrast, cores with platinum sputtered coatings were completelyprotected throughout the same period. This demonstrates the in vitroeffectiveness of the very thin sputtered catalyst on the surface of thegraft to protect the graft indicator layer from oxidation due to highambient concentrations of hydrogen peroxide.

The purpose of this invention is to protect against major signal losscaused by oxidation both during wound healing as well as lower-levelchronic oxidation during the lifetime of the sensor. If a device isprotected from oxidation that occurs during wound healing, it becomesthe lower-level chronic oxidation that ultimately establishes the usefullife of a sensor implant. A protective layer preventing oxidation fromlong-term foreign body response will greatly extend the useful life ofthe sensor.

An additional important performance factor for in vivo devices is theextension of time between calibration. A device with a longerrecalibration interval is better for a user, both in cost and in healthdue to the increased life of the sensor. Typically a sensor that isotherwise mechanically, chemically, and electrically stable will remainin calibration for as long as analyte concentration is the onlyvariable. However, under chronic oxidation, a steady degradative changeis imposed on the device by oxidation of indicator or materials ofconstruction, thereby causing a mechanical and/or chemical change beyondthat which is attributed only to analyte changes. For a sensor using achemical or biochemical transduction system, progressive oxidation ofindicator amounts to a second variable that is manifest as signal driftor decay over time. Any signal movement that is not caused by theanalyte, or that is understood and compensated for by the signalprocessing system causes the sensor to drift out of calibration and mustbe re-calibrated to back within its performance standard. Byeliminating, or even slowing down oxidation of indicator or any materialcomponent within the sensor transduction system, the recalibrationinterval is extended. Some in vivo sensors can require as many as threerecalibrations per 24 hour period. A sensor that needs to berecalibrated for significantly longer intervals, such as only once perweek, per month, or per quarter, would have much higher value to users.In embodiments of the invention, if the indicator molecules aresufficiently protected such that there is not a drastic loss of signal,or if degradative change is stopped entirely, then the only calibrationneeded will be at the time of manufacture.

A study was conducted to evaluate the protection of an implanted sensorfrom ROS degradation in humans by use of a plasma sputtered platinumporous catalytic diffusion barrier installed onto the surface of thesensor. In this study, twenty one sensors were sputtered with metallicplatinum to a depth of 3 nanometers using an Electron MicroscopySciences EMS150TS. The plasma chamber of the EMS150TS was flushed,evacuated, and backfilled with argon gas to 0.01 mbar. The current wasset at 25 mA, and the platinum thickness was determined by a thicknessmonitor mounted within the chamber. After platinum deposition, sensorswere packaged for sterilization by ethylene oxide and stored at 70%relative humidity (RH).

All twenty one experimental, platinum sputtered sensors were implantedinto the subcutaneous space above the fascia in the dorsal wrist areafor twelve human (type 1 diabetic) volunteers. Similarly, 12 controlsensors without platinum treatment were implanted into the same wristlocation for seven type 1 diabetic human volunteers. The subjectidentification numbers include either an “LA” or an “RA” to designatewhether that sensor was implanted in the left arm or right arm,respectively. The data presented is the modulation taken from thesensor's wireless telemetry feed to an external reader.

Table 1 presents the comparative results from in vivo implants. The datafrom the control sensors was reported at days 7, 10, 16, 23, and 28during implant. The data from the experimental, platinum sputteredsensors was reported at days 3, 13, 21, 26, and 29 after implant.

TABLE 1 Subject Modulation remaining at each read session Controls Lot #Day 7 Day 10 Day 16 Day 23 Day 28 D05 LA 03052011 33% 32% 31% 19% 18%D05 RA 03252011  0%  0%  0%  0%  0% D06 LA 03052011 66% 56% 55% 53% 52%D06 RA 03252011  0%  0%  0%  0%  0% D07 LA 03052011 59% 58% 57% 50% 48%D07 RA 03252011 72% 71% 34% 23% 22% D08 LA 03052011 86% 85% 37% 33% 30%D08 RA 03252011 22% 22% 21% 20% 20% D09 LA 03052011 53% 52% 51% 49% 48%D09 RA 03252011  0%  0%  0%  0%  0% D10 RA 03252011 47% 46% 45% 41% 40%D11 LA 03252011  0%  0%  0%  0%  0% Combined 37% ± 32% 35% ± 31% 28% ±23% 24% ± 21% 23% ± 20% Platinum Sputtered Day 3 Day 13 Day 21 Day 26Day 29 D18 LA 05202011 98% 94% 91% 90% 88% D18 RA 05202011 94% 91% 88%87% 85% D19 LA 05202011 92% 90% 77% 75% 74% D19 RA 05202011 91% 78% 76%75% 73% D20 LA 05202011 72% 69% 67% 66% 65% D21 RA 05202011 87% 83% 80%79% 77% D22 LA 05202011 90% 81% 79% 77% 75% D23 LA 06032011 92% 88% 85%83% 82% D23 RA 05202011 84% 74% 66% 62% 60% D24 LA 06032011 98% 92% 88%85% 84% D24 RA 05202011 85% 74% 67% 63% 60% D25 LA 06032011 91% 84% 79%76% 74% D25 RA 05202011 89% 83% 78% 76% 74% D26 LA 06032011 99% 94% 91%89% 88% D26 RA 06032011 99% 94% 91% 89% 88% D27 LA 07222011 99% 94% 91%89% 88% D27 RA 07222011 94% 90% 87% 85% 84% D28 LA 07222011 75% 71% 67%65% 64% D28 RA 07222011 95% 91% 88% 86% 85% D29 LA 07222011 99% 95% 91%90% 88% D29 RA 07222011 95% 90% 86% 84% 83% Combined  91% ± 7.5%  86% ±8.3%  82% ± 8.9%  80% ± 9.3%  78% ± 9.5%

As can be seen from the data in Table 1, the platinum surface diffusionbarrier preserves signal relative to the untreated devices by a factorof more than double. Importantly, no sensors using the platinum sputtertreatment are degraded to zero as is typical in the untreated group. Thedata shows that platinum is providing local protection of the indicatorsystem within the microenvironment of the indicator graft withoutinterfering with normal heal-up reactions requiring ROS that may beongoing in the surroundings. Further, the significant sensor-to-sensorand/or subject-to-subject variability in modulation remaining displayedin the control group is not seen in the experimental, platinum sputteredgroup.

Table 2 presents expected life time data for the in vivo implants inTable 1. The expected life time of the implant is calculated by a curvefit extrapolation. In Table 2, the columns give data in terms of a rangeof days and a number of visits. The data collected from within specifiedrange of days was used to calculate and extrapolate the expected usefullife of the sensor before its signal would drop too low to maintainaccuracy specification. After implant of a device or material, thenatural heal-up process continues which includes ROS of the inflammationresponse. Thus, a calculation made at a later time interval within orafter the heal-up period might be expected to be more representative ofthe full lifetime of the implanted device or material than one madeclose after implant when healing is just getting started. Data usedtoward the end of the period would be expected to be more settled andmore accurate than data from earlier because the heal-up process is moresettled toward the end of the period. The visits noted in each columnrefer to the number of visits into the clinic the patient has madepost-implant by the time the measurements used in the calculation fromthe patient's implant are taken.

TABLE 2 Expected life time (days) Subject Day 7-10 Day 7-16 Day 7-23 Day7-28 Day 10-28 Day 16-28 Controls Lot # (2 visits) (3 visits) (4 visits)(5 visits) (4 visits) (3 visits) D05 LA 03052011 335 335 77 79 73 65 D05RA 03252011 0 0 0 0 0 0 D06 LA 03052011 63 146 215 253 377 398 D06 RA03252011 0 0 0 0 0 0 D07 LA 03052011 370 389 225 228 214 190 D07 RA03252011 395 45 45 54 55 88 D08 LA 03052011 403 43 54 66 70 123 D08 RA03252011 218 234 238 239 241 242 D09 LA 03052011 320 368 374 377 383 382D09 RA 03252011 0 0 0 0 0 0 D10 RA 03252011 359 360 242 243 222 211 D11LA 03252011 0 0 0 0 0 0 Combined 205 ± 177 160 ± 166 123 ± 129 128 ± 132136 ± 145 142 ± 145 Platinum Day 3-13 Day 3-21 Day 3-25 Day 3-29 Day13-29 Day 21-29 Sputtered (2 visits) (3 visits) (4 visits) (5 visits) (4visits) (3 visits) D18 LA 05202011 418 419 420 420 421 422 D18 RA05202011 405 407 408 409 411 412 D19 LA 05202011 443 250 252 264 239 431D19 RA 05202011 151 214 244 272 424 431 D20 LA 05202011 403 403 403 403403 403 D21 RA 05202011 398 413 417 420 430 430 D22 LA 05202011 268 328352 357 422 379 D23 LA 06032011 439 438 438 435 433 431 D23 RA 05202011126 142 184 211 246 319 D24 LA 06032011 205 346 371 395 469 470 D24 RA05202011 81 188 176 191 232 188 D25 LA 06032011 107 198 262 307 428 440D25 RA 05202011 123 218 282 324 431 441 D26 LA 06032011 467 469 470 470470 468 D26 RA 06032011 453 454 455 453 453 451 D27 LA 07222011 463 461461 461 460 460 D27 RA 07222011 511 513 514 513 513 512 D28 LA 07222011182 294 353 353 442 451 D28 RA 07222011 469 476 479 475 475 471 D29 LA07222011 449 447 449 450 450 451 D29 RA 07222011 248 348 394 420 466 469Combined 324 ± 149 354 ± 113 371 ± 100 381 ± 89  415 ± 78 425 ± 67 

As can be seen from the calculated data in Table 2, the expectedlifetime of an implant, as determined from the modulation of the sensor,greatly increases when the implant is protected with a platinum barrierlayer sputtered onto its surface.

In other aspects, the present invention has application to anybiomaterial or implanted material or device, where such materials ordevices may be passive, structural, or functional in nature, that may besusceptible in some way to in vivo inflammation reaction. Exemplary,non-limiting, applications of this invention are set forth below.

Continuous glucose monitors other than the embodiments disclosed abovein this application would also likely benefit from this invention. Forexample, transcutaneous needle-type indwelling continuous glucosemonitor (CGM) devices also interface directly with subcutaneous tissuein such a way as to stimulate local inflammation and foreign bodyresponse. The body would respond to these intrusions of foreign materialand mechanical tissue insult just as a completely implantable device. Itis expected that hydrogen peroxide and ROS would have the same effect incausing substantial oxidative damage to any chemically or biochemicallytransduced system and thus benefit from the invention.

In particular, glucose oxidase sensors that use hydrogen peroxide as apart of their sensing functionality often need to prevent hydrogenperoxide from freely entering an in vivo environment. Such sensors mayuse additional catalyses to degrade hydrogen peroxide or use a laminateas a part of the sensor to prevent hydrogen peroxide from enteringand/or aggregating in an in vivo environment. The catalytic protectiondisclosed in this application may be applied to such devices.

All implants, whether they are active (such as a sensor) or passivematerials (such as in orthopedic or cosmetic applications), are exposedto living tissue and fluids and are thus susceptible to oxidation viathe body's normal response system. Living cells produce reactive oxygenspecies such as hydrogen peroxide in what is commonly known as localizedinflammation and foreign body response stimulated either directly by thematerial/device implanted, and/or by the inevitable tissue disruptionrepair caused by physically implanting the material or device. Typicallydevices or materials are compromised by oxidative assault in livingtissue. Such devices can include, without limitation, pacemakers, jointimplants, bandages, orthopedic devices, cosmetic or reconstructivesurgery implants, or time release porous polymer material implants forleaching drug delivery. Exemplary implanted biomaterials can includematerials such as polyurethane and other polymers. The compromise may bemanifest as structural weakening, degradation in properties, loss offunctionality, or alteration in the chemical structure itself to adifferent composition than intended. These oxidation assaults arenormal, but often either shorten the useful life, compromise optimalperformance, or cause the outright failure of the implant. According tothe present invention, the application of very thin, in some embodimentssubmicron, layers of a protective barrier from about 0.5 nm to about 2.5mm in thickness applied to implanted materials of exposure can protectthe device locally from oxidation by ROS.

In an alternative embodiment of the invention, as seen in FIG. 18, acatalytic barrier that prevents ROS driven oxidation may be applied to apacemaker, comprising at least an electrical generator 1801 of thepacemaker and pacemaker leads 1802 implanted to regulate a heart 1800. Apacemaker is subject to inflammation response and to chronicforeign-body response and the associated ROS driven oxidation. Inparticular, a catalytic barrier can be applied to pacemaker leads 1802in the form of a structural encasement at least partially encasing thepacemaker leads 1802, or a coating applied to the pacemaker leads 1802potentially through sputter deposition, in accordance with embodimentsof the present invention.

Alternatively, an inflammation reaction can occur on the externalsurface of skin in response to stimuli including, without limitation,polymer adhesives in EEG or EKG patches, watch bands, earrings, or anyother material to which a human has an acute sensitivity or allergy.According to the present invention, the application of very thin, insome embodiments submicron, layers of a protective barrier from about0.5 nm to about 2.5 mm in thickness applied to such materials canprotect such materials from ROS.

Any other exposure within other non-implant environments or applicationswhere exposure to hydrogen peroxide (ROS) may compromise, or degrade theperformance of a material or molecule, or device functionality, wouldalso benefit from this invention. Molecules, microcircuit, optical,chemical, or micromechanical constructs may be encased within porousprotective layers, metalized from the outside, and allow free diffusionaccess to the intended molecules but provide a protective barrieragainst damaging peroxides and other ROS which are degraded to harmlessoxygen and water at the layer of metallization. Devices benefiting fromprotection but not requiring diffusive access to analytes, such asdevices with RFID components, can benefit by direct metallization ontothe surface of the material without a porous coating. Further,applications that do not apply a metal film to a porous surface may havea thickness that is appropriate to adequately protect a more uniformsurface.

While the invention has been described in detail above, the invention isnot intended to be limited to the specific embodiments as described. Itis evident that those skilled in the art may now make numerous uses andmodifications of and departures from the specific embodiments describedherein without departing from the inventive concepts.

The invention claimed is:
 1. A sensor having an in vivo functionality,the sensor comprising: a sensor body encasing a photosensitive detectorelement and a light source, the sensor body comprising an exteriorsurface and a groove in the exterior surface; a porous sensor graft onat least the groove in the exterior surface of the sensor body, whereinthe porous graft comprises one or more indicator macromolecules; and aprotective material in close proximity to the porous sensor graft andsurrounding one or more of (i) a portion or all of the porous sensorgraft and (ii) a portion of the exterior surface of the sensor body,wherein: (1) the protective material prevents or reduces degradation orinterference of the porous sensor graft due to inflammation reactionsand/or foreign body response; (2) the protective material comprises ametal or metal oxide which catalytically decomposes or inactivates invivo reactive oxygen species or biological oxidizers; and (3) theprotective material does not completely surround the sensor body.
 2. Thesensor of claim 1, wherein the sensor is for monitoring glucose levels.3. The sensor of claim 1, wherein the one or more indicatormacromolecules comprises a phenylboronic acid residue.
 4. The sensor ofclaim 1, wherein the metal or metal oxide comprises silver, palladium,platinum, manganese, or alloys, or gold-inclusive alloys, orcombinations thereof.
 5. The sensor of claim 1, wherein the poroussensor graft is made from a material that is sensitive to, or issusceptible to damage from, oxidation.
 6. The sensor of claim 1, whereinthe protective material is in close proximity to at least a part of thesensor body that comprises a polymer.
 7. The sensor of claim 1, whereinthe protective material is from about 0.5 nm to about 2.5 mm thick.
 8. Asensor having an in vivo functionality, the sensor comprising: a sensorbody encasing a photosensitive detector element and a light source, thesensor body comprising an exterior surface and having a saddle-cut shapein the exterior surface; a porous sensor graft on at least a portion ofthe exterior surface of the sensor body, wherein the porous graftcomprises one or more indicator macromolecules; and a layer ofprotective coating applied onto one or more of (i) a portion or all ofthe porous sensor graft and (ii) a portion of the exterior surface ofthe sensor body, wherein: (1) the protective coating prevents or reducesdegradation or interference of the porous sensor graft from inflammationreactions and/or foreign body response; (2) the protective coatingcomprises a metal or metal oxide which catalytically decomposes orinactivates in vivo reactive oxygen species or biological oxidizers; and(3) the layer of protective coating does not completely surround thesensor body.
 9. The sensor of claim 8, wherein the sensor is formonitoring glucose levels.
 10. The sensor of claim 8, wherein the one ormore indicator macromolecules comprises a phenylboronic acid residue.11. The sensor of claim 8, wherein the protective coating is applied bysputter deposition.
 12. The sensor of claim 8, wherein the metal ormetal oxide comprises silver, palladium, platinum, manganese, or alloys,or gold-inclusive alloys, or combinations thereof.
 13. The sensor ofclaim 8, wherein the protective coating is from about 0.5 nm to about500 nm thick.
 14. The sensor of claim 8, wherein the protective coatingis from about 1 nm to about 20 nm thick.
 15. The sensor of claim 8,wherein the protective coating is from about 3 nm to about 6 nm thick.16. The sensor of claim 8, wherein the protective coating is at leastabout 1 nm thick.
 17. The sensor of claim 8, wherein the porous sensorgraft is made from a material that is sensitive to, or is susceptible todamage from, oxidation.
 18. The sensor of claim 8, wherein theprotective coating is applied onto at least a part of the sensor bodythat comprises a polymer.
 19. The sensor of claim 8, wherein the sensorhas an in vivo functionality for a substantially elongated period oftime, as compared to the useful life of a separate material with in vivoutility but without the layer of protective coating, following implantin an environment where the sensor is exposed to inflammation reactionsand/or foreign body response.
 20. A method for using a sensor for invivo applications comprising: implanting a sensor in a subject body,wherein the sensor has an in vivo functionality and comprises a sensorbody encasing a photosensitive detector element and a light source,comprising an exterior surface, and having a saddle-cut shape in theexterior surface; a porous sensor graft on at least a portion of theexterior surface of the sensor body, the porous graft comprising one ormore indicator macromolecules; and a layer of a protective coating onone or more of (i) a portion or all of the porous sensor graft and (ii)a portion of the exterior surface of the sensor body, wherein: (1) theprotective coating prevents or reduces degradation or interference ofthe porous sensor graft due to inflammation reactions and/or foreignbody response; (2) the protective coating comprises a metal or metaloxide which catalytically decomposes or inactivates in vivo reactiveoxygen species or biological oxidizers; and (3) the protective coatingdoes not completely surround the sensor body.
 21. The method of claim20, wherein the in vivo functionality of the sensor is to operate as asensor designed to detect glucose.
 22. The method of claim 20, whereinthe one or more indicator molecules comprises a phenylboronic acidresidue.
 23. The method of claim 20, wherein the protective coating isapplied by sputter deposition.
 24. The method of claim 20, wherein themetal or metal oxide comprises silver, palladium, platinum, manganese,or alloys, or gold-inclusive alloys, or combinations thereof.
 25. Themethod of claim 20, wherein the protective coating is from about 0.5 nmto about 500 nm thick.
 26. The method of claim 20, wherein theprotective coating is from about 1 nm to about 20 nm thick.
 27. Themethod of claim 20, wherein the protective coating is from about 3 nm toabout 6 nm thick.
 28. The method of claim 20, wherein the protectivecoating is at least about 1 nm thick.
 29. The method of claim 20,wherein the in vivo functionality of the sensor is to operate as asensor designed to detect a target analyte.
 30. The method of claim 20,wherein the porous sensor graft is made from a material that issensitive to, or is susceptible to damage from, oxidation.
 31. Themethod of claim 20, wherein the protective coating is applied onto atleast a part of the sensor body that comprises a polymer.
 32. The methodof claim 20, wherein the sensor has an in vivo functionality for asubstantially elongated period of time, as compared to the useful lifeof a separate material with in vivo utility but without the layer ofprotective coating, following implant in an environment where the sensoris exposed to inflammation reactions and/or foreign body response.
 33. Amethod for detecting the presence or concentration of an analyte in anin vivo sample, said method comprising: (a) exposing the sample to aporous sensor graft of a sensor, the porous sensor graft having adetectable quality that changes when the porous sensor graft is exposedto the analyte, said sensor comprising a sensor body encasing aphotosensitive detector element and a light source, comprising anexterior surface, and having a saddle-cut shape in the exterior surface;a porous sensor graft on at least a portion of the exterior surface ofthe sensor body, the porous graft comprising one or more indicatormacromolecules; and a layer of protective coating applied onto one ormore of (i) a portion or all of the porous sensor graft and (ii) aportion of the exterior surface of the sensor body, wherein: (1) theprotective coating prevents or reduces degradation or interference ofthe porous sensor graft from inflammation reactions and/or foreign bodyresponse; (2) the protective coating comprises a metal or metal oxidewhich catalytically decomposes or inactivates in vivo reactive oxygenspecies or biological oxidizers; and (3) the protective coating does notcompletely surround the sensor body, such that the sensor has enhancedresistance to degradation or interference as compared to a correspondingsensor without the protective coating; and (b) measuring any change insaid detectable quality to thereby determine the presence orconcentration of said analyte in said sample.
 34. The method of claim33, wherein the analyte is glucose.
 35. The method of claim 33, whereinthe one or more indicator molecules comprises a phenylboronic acidresidue.
 36. The method of claim 33, wherein the protective coating isapplied by sputter deposition.
 37. The method of claim 33, wherein themetal or metal oxide comprises silver, palladium, platinum, manganese,or alloys, or gold-inclusive alloys or combinations thereof.
 38. Themethod of claim 33, wherein the protective coating is from about 0.5 nmto about 500 nm thick.
 39. The method of claim 33, wherein theprotective coating is from about 1 nm to about 20 nm thick.
 40. Themethod of claim 33, wherein the protective coating is from about 3 nm toabout 6 nm thick.
 41. The method of claim 33, wherein the protectivecoating is at least about 1 nm thick.
 42. The method of claim 33,wherein the porous sensor graft is made from a material that issensitive to, or is susceptible to damage from, oxidation.
 43. Themethod of claim 33, wherein the protective coating is applied onto atleast a part of one or more of the sensor body that comprises a polymer.44. The method of claim 33, wherein the sensor has an in vivofunctionality for a substantially elongated period of time, as comparedto the useful life of a separate material with in vivo utility butwithout the layer of protective coating, following implant in anenvironment where the sensor is exposed to inflammation reactions and/orforeign body response.
 45. An implantable glucose sensor for determiningthe presence or concentration of glucose in an animal, said sensorcomprising: (a) a sensor body having an outer surface surrounding saidsensor body and a groove in the outer surface; (b) a radiation source insaid sensor body which emits radiation within said sensor body; (c) anindicator element that is affected by the presence or concentration ofglucose in said animal, said indicator element being on at least thegroove in said outer surface of said sensor body; (d) a photosensitiveelement located in said sensor body and positioned to receive radiationwithin the sensor body, said photosensitive element configured togenerate a signal responsive to radiation received from said indicatorelement and which is indicative of the presence or concentration ofglucose in said animal; and (e) a protective barrier comprising silver,palladium, platinum, manganese, or alloys, or gold-inclusive alloys, orcombinations thereof, surrounding one or more of (i) a portion or all ofsaid indicator element and (ii) a portion of said outer surface of saidsensor body, wherein the protective barrier surrounds one or more of (1)a portion or all of said indicator element and (2) a portion of saidouter surface of said sensor body, and the protective barrier does notcompletely surround the sensor body.
 46. The sensor of claim 45, whereinthe outer surface is comprised of a polymer.
 47. The sensor of claim 45,wherein the indicator element comprises at least one indicatormacromolecule.
 48. The sensor of claim 45, wherein the protectivebarrier is further comprised of oxides of silver, platinum, palladium,manganese, alloys, or gold-inclusive alloys, or combinations thereof.49. The sensor of claim 1, wherein sensor body has a 360 degree cutshape.
 50. The sensor of claim 1, wherein the sensor body has asaddle-cut shape.
 51. The sensor of claim 1, wherein the protectivematerial is applied by sputter deposition.
 52. The sensor of claim 1,wherein the protective material is a structure that comprises a coil,mesh, weave, or perforated and/or slotted structure at least partiallysurrounding the device.
 53. The sensor of claim 45, wherein theprotective barrier is a structural encasement in the form of a wire,mesh, weave, or a perforated and/or slotted encasement at leastpartially surrounding said porous graft.
 54. The sensor of claim 45,wherein the protective barrier is a coating directly covering at least apart of said porous graft.
 55. The sensor of claim 45, wherein sensorbody has a 360 degree cut shape.
 56. The sensor of claim 45, wherein thesensor body has a saddle-cut shape.
 57. The sensor of claim 45, whereinthe protective barrier is applied by sputter deposition.